Accumulation of senescent cells in aging primates

I currently work on a phenomenon known as cellular senescence, which is a permanent growth arrest caused by telomere dysfunction (e.g., the critically shortened telomeres that arise after many cell divisions) and also by other kinds of stress (particularly genotoxic damage).

One of the active controversies in this sub-field of biogerontology is, somewhat paradoxically, whether it’s part of biogerontology at all: While senescence certainly arises as cells get older in culture, and while there’s a good story to be told about how senescent cells could contribute to age related decline in tissue function, it’s not yet fully clear to what extent the phenomenon actually plays a role in physiological aging of intact animals.

Until recently, the cells themselves were difficult to detect in vivo (more precisely, in biopsies taken longitudinally from a single animal over the course of aging), because senescence markers were few in number and a little twitchy to work with — to put it succinctly, using high-background techniques to detect low-abundance cells is a frustrating and unenviable task.

As more reliable markers have become available, however, several groups have made significant progress toward determining whether senescent cells play a role in aging. For instance, Jeyapalan et al. have advanced the circumstantial case for a role in aging by showing that senescent cells accumulate in the mitotic tissues of aging primates.

Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over 40 years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA. In skeletal muscle, a postmitotic tissue, only a small percentage of myonuclei containing damaged telomeres were detected regardless of animal age. The presence of senescent cells in mitotic tissues might therefore be a contributing factor to aging and age related pathology and provides further evidence that cellular senescence is a physiological event.

Other groups (including ours) are working to characterize at a molecular level the effect that senescent cells have on the tissue microenvironment, both from the standpoint of facilitation of carcinogenesis and age-related deterioration. Meanwhile, placing the suspect at the scene of the crime is a critical advance in the overall story.

2 Responses to “Accumulation of senescent cells in aging primates”

The significance of cellular senescence as a cause for aging is yet to be determined. To answer the question, we need to develop model organisms in which senescent cells can be removed, and then ask whether they age more slowly. That work is currently ongoing in multiple labs around the world.